Work conducted in my laboratory has demonstrated that microbial infections induced by numerous pathogenic agents cause alterations in normal sleep patterns, and that facets of the immune response to microbial challenge are likely to mediate these behavioral effects. Identifying the factors that cause fatigue and excessive or disturbed sleep during microbial infections and developing effective interventions for these disabling symptoms could improve the economic well-being and quality of life of many individuals. My long-term goal is to define the genetic and inflammatory mechanisms that mediate fatigue and altered sleep propensity during infectious disease. To that end, I recently completed an analysis of genetic contributions to altered sleep patterns in influenza-infected mice. My preliminary data indicate that a discrete subset of genes is likely to account for large and consistent differences in influenza-induced sleep in different strains of inbred mice. This application proposes to build on that work by identifying the genetic and pathologic mechanisms that mediate sleep responses to other types of microbial challenges and by integrating the new data with our previous findings. A genome-wide approach to identifying candidate genes will be applied in the proposed aims. As the critical first step in identifying genes that regulate infection-induced alterations in sleep, we will characterize the sleep patterns of prototypic strains of mice after specific microbial challenges. We will use those data to select the most efficient strategies for mapping quantitative trait loci for infection-related sleep phenotypes using recombinant inbred mice. Identifying the genes that modulate infection-induced sleep is an important step toward discovering gene products that influence disease susceptibility and symptomatology. Studying the mechanisms by which genes and their products modulate sleep will ultimately improve our understanding of processes that control normal sleep and contribute to sleep disorders.